February 01, 2000
Photoreceptor Gene Mutation Discovered
HHMI researchers have discovered the cause of enhanced S-cone
syndrome (ESCS), a disorder that makes those affected sensitive to blue
light and susceptible to developing night blindness at an early
age.
A research team led by Val C.
Sheffield, an HHMI investigator at the University of Iowa College
of Medicine, discovered that 94 percent of DNA samples from
ESCS-affected individuals showed mutations in NR2E3, a
photoreceptor gene that is also known as PNR
(photoreceptor-specific nuclear receptor).
“I think the main interest in this paper will be the insight that it might bring to understanding the signaling pathways that determine cell type in the embryonic retina.”
Val C. Sheffield
The research team, which included lead author Neena B. Haider, an
HHMI-supported graduate student in Sheffield's lab, Samuel G. Jacobson
at the Scheie Eye Institute at the University of Pennsylvania, Edwin M.
Stone from the department of ophthalmology at Iowa, and other
collaborators, published its findings in the February 2000 issue of the
journal Nature Genetics.
Photoreceptors are specialized light-sensitive nerve cells that line
the retina. Humans have two types of photoreceptors, called rods and
cones. Rods mediate black and white vision and are used mainly at
night. During the day, however, humans depend on cones for color
vision. Cones come in three types – red, green, and blue –
that are sensitive to different wavelengths of light.
ESCS is a rare degenerative disease of the retina. Patients with
ESCS suffer from night blindness and increased sensitivity to blue
light. These observations led researchers to speculate that ESCS is
caused by mistakes early in photoreceptor development that cause an
overabundance of blue cones relative to the number of red and green
cones.
Sheffield's lab, which focuses on identifying genes that cause human
hereditary diseases, especially hereditary blindness, discovered the
ESCS mutations while studying another retinal disorder called Bardet
Biedl syndrome (BB).
While sequencing different regions of the genome associated with BB
they located a gene called PNR. The gene seemed an interesting
candidate for BB because it was expressed in the eye, but Sheffield and
his colleagues could not find any PNR mutations in patients with
BB. They did, however, think PNR a good candidate for other eye
diseases, so they screened nearly 400 DNA samples from people with
other eye disorders, and found two samples that possibly contained a
PNR mutation.
"Interestingly, these patients had ESCS," recalls Sheffield. "Now we
had a hypothesis that mutations in this gene cause this specific
syndrome."
To increase their sample size, they tested 35 ESCS-affected
individuals from 29 families, obtaining samples from collaborators. "Lo
and behold we found that nearly every sample had a mutation," remarks
Sheffield.
Sheffield and his colleagues also found that the expression of
NR2E3 is specific to the nuclear layer of the retina, which is
lined by the nuclei of photoreceptors.
"A lot of interesting biology comes out of rare diseases and rare
mutations," says Sheffield. "I think the main interest in this paper
will be the insight that it might bring to understanding the signaling
pathways that determine cell type in the embryonic retina." Right now,
researchers do not know how precursor photoreceptors reach their
ultimate cell type.
"ESCS is interesting in what it might imply for how photoreceptor
pattern and fate gets set up in the eye," says Contance
Cepko, an HHMI investigator at Harvard Medical School, who authored
an accompanying News & Views article in Nature
Genetics. "The discovery of any mutation that affects that process
is important."
Discovering the molecular signals that determine why one cell
becomes a rod or a cone, and how cone cells become blue-, green- or
red-sensitive are important questions in the study of eye development.
"This disease may provide some answers to these questions," says
Sheffield. "Now we've found a mutation and a gene that would indicate
that NR2E3 is one of the signaling genes in retinal
development."
As in most scientific discoveries, the findings of this paper now
create more questions than answers. If signaling mistakes in the
expression of NR2E3 are the cause of ESCS, how might this
happen? One hypothesis is that cone cells become blue by default unless
they receive a signal to become red or green. Another hypothesis is
that NR2E3 mutations alter a photoreceptor's fate, causing cells
that would normally develop as rods to become cones instead.
To find out what is really happening in ESCS patients, says Cepko,
researchers might have to await an animal model of the disorder.
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